Osteoporosis/bone fragility| JOURNAL OF GERONTOLOGY AND GERIATRICS

1. RECOMMENDATIONS

1. In elderly subjects with T2DM, the identification and management of diabetic patients with increased fracture risk should follow the algorithm proposed by the International Osteoporosis Foundation (IOF), as shown in Figure 1 (grade: 1A) ¹. All of these patients should undergo a dual-energy x-ray absorptiometry (DXA) scan to measure bone mineral density. A DXA scan is also indicated for individuals older than 50 years and/or individuals with a previous fragility fracture or treated with thiazolidinediones. The 2020 American Diabetes Association (ADA) standards of care recognize that the risk of fracture is significantly higher in individuals with DM, for both genders and all age groups, and recommend assessing fracture history and risk factors for fracture, especially in elderly DM patients ². DXA-derived t-scores should be corrected by a factor of 0.5 in DM patients (e.g., t-score < -2.0 in a patient with DM is equivalent to < -2.5 in a non-diabetic patient) (grade: 2A) ³.
2. Regardless of DXA parameters, it is important to assess fracture risk with patient interview and the Fracture Risk Assessment Tool (FRAX^®) during screening visits, especially for patients with a long diabetes duration. When using FRAX^® in the assessment of DM patients, the rheumatoid arthritis option should be checked (grade: 2A) ^1,4. If results are above the suggested cutoffs, the patient should be monitored with repeated DXA and FRAX^® assessments at regular intervals of 2-3 years ¹.
3. Patients with a T-score < -2.0, or above the FRAX algorithm’s treatment threshold, should be started on anti-resorptive therapy. Drugs of first choice are bisphosphonates (alendronate or risedronate) (grade: 2A) ^5,6. Although there is less evidence about denosumab, it remains a valid choice for patients who cannot tolerate bisphosphonates or have chronic kidney disease.
4. It is also recommended that vitamin D deficiency be prevented by providing the recommended daily intakes of 800 IU per day for elderly patients or, in vitamin D deficiency, by providing higher doses without exceeding the maximum tolerability dose of 4000 IU per day (grade: 4A) ⁷. Vitamin D supplementation strategies should aim at the optimal serum concentration of 25(OH)D in frail geriatric patients, i.e., > 30 ng/ml.

2. STRENGTH OF THE RECOMMENDATIONS

The quality of the evidence is moderate and supported by published evidence.

3. SUPPORTING EVIDENCE

See appendix.

4. AREAS OF UNCERTAINTY AND FUTURE PERSPECTIVES

The clinical management of patients with diabetic bone fragility is complex and still suboptimal. Interpretation of the clinical significance of BMD is difficult, but BMD should be assessed on a regular basis to monitor bone loss. Evidence supporting the use of anti-osteoporotic treatment in DM patients is relatively scarce, but treatment should not be neglected. Romosozumab, a novel bone anabolic agent, is a promising option that needs to be tested in future studies. The effect of vitamin D on muscle health and falls prevention remains controversial.

APPENDIX

DM and osteoporosis are two chronic diseases with a high prevalence, especially in the geriatric population. These two conditions often coexist and are characterized by changes in mineral density, growth, and bone remodeling, as well as by an increased fracture risk. There is increasing evidence that bone fragility should be included among diabetes complications ⁸.

Diabetes mellitus has a higher prevalence in persons aged 70-79 years ⁹, an age group where a significant proportion of individuals also have osteoporosis. It is estimated that osteoporosis affected 22 million women and 5.5 million men in the European Union in 2010 ¹⁰. In older persons, especially those with DM, other factors contribute exponentially to fracture risk, such as changes in bone quality, diabetic complications (e.g., diabetic retinopathy and/or diabetic nephropathy), drug therapies, immobility, frailty, and comorbid conditions that increase the risk of falls ¹¹.

Different mechanisms contribute to changes in bone health in DM. Non-enzymatic glycation of type I collagen, low bone turnover, chronic low-grade inflammation, and microvascular alterations are all factors leading to abnormalities in bone micro- and macro-architecture that underpin reduced resistance to mechanical stress ⁸. Bone structural changes in T2DM include increased cortical porosity and reduced cortical thickness. Studies have shown different patterns of bone mineral density in DM, which is generally reduced in T1DM and normal or increased in T2DM. In T2DM patients, bone mineral density is 5-10% higher than in persons without DM ¹². However, despite high bone mineral density, several studies have shown that bone quality is compromised in T2DM patients, particularly in older people ¹³. This explains the paradox of an increased risk of fracture associated with T2DM despite patients having high bone mineral density ¹⁴. Typical diabetic complications such as diabetic neuropathy leading to poor balance, diabetic retinopathy, and impaired kidney function are all factors associated with increased risk of falls and fractures. In addition, serum markers of bone turnover are generally lower in DM patients than in normoglycemic individuals, raising concerns that anti-resorptive drugs used to treat osteoporosis may further suppress bone remodeling in patients with DM. Although the evidence is limited, data from clinical trials suggest that osteoporosis drugs are effective in DM patients.

Bisphosphonates are potent anti-resorptive medications and their effectiveness in preventing fractures has been widely demonstrated in clinical trials. Among the few available data in diabetic patients, a post-hoc analysis from the FIT trial showed that 3 years of treatment with alendronate increased bone mineral density to levels similar to non-diabetic individuals ¹⁵. These findings are limited to BMD and in a subgroup of 297 DM patients without information on fracture risk. Even less evidence is available for denosumab, an anti-resorptive agent that targets the RANKL, inhibiting osteoclast activation. A post-hoc analysis of the FREEDOM trial has proved that denosumab significantly increased BMD and lowered vertebral fracture risk, while no effect was observed on non-vertebral fractures (Ferrari, Bone 2020). A favorable effect in DM patients has also been observed with teriparatide, an anabolic agent that increases both bone formation and, to a lesser extent, bone resorption. Teriparatide could therefore play a particularly positive role in the prevention of bone fragility in DM, which is characterized by reduced bone remodeling. An analysis of four observational studies including more than 8,800 patients treated with teriparatide (20 μg per day for up to 24 months) showed a significant reduction in all fracture types after six months of treatment, with higher efficacy in DM than non-diabetic individuals ¹⁶.

On the other hand, different drugs used to treat DM can affect bone health. Indeed, insulin treatment is another risk factor for falls and fractures, probably due to an increase in hypoglycemic events. The adverse effects of thiazolidinediones on bone health are well known. These drugs are not recommended in post-menopausal women or in elderly men ^17,19. SGLT2-inobitors such as canagliflozin, which was shown to increase the risk of fractures in the CANVAS study, should be used with caution in the elderly. However, this finding was not confirmed in other randomized studies ^2,18-21. Particular care should also be taken with drugs that can cause hypoglycemia, such as insulin, sulfonylureas, or glinides (grade: 3A) ².

Finally, DM patients, especially if elderly, exhibit higher rates of hypovitaminosis D than non-diabetic patients ²². Vitamin D plays a central role in maintaining bone health and in reducing the risk of falls ²³, and maintaining adequate vitamin D levels is recommended during treatment with anti-osteoporotic drugs to support their efficacy. Vitamin D status should be monitored over time in patients with high risk of hypovitaminosis-D, measuring serum concentration of 25-hydroxyvitamin D (25OHD). More importantly, it is crucial that all elderly DM patients achieve an intake of at least 800 UI of vitamin D per day, which can be increased up to 4000 UI according to specific needs.

Acknowledgement

None.

Ethical consideration

None.

Funding

None.

Conflict of interest

The Author declares no conflict of interest.

Figures and tables

References

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